PROJECT SUMMARY Age-related dysfunction of cerebral blood flow regulation plays an important role in the pathophysiology of brain aging and likely renders the aging brain more susceptible to the damaging effects of comorbid conditions, such as hypertension, diabetes, and hypercholesterolemia. Impairments in two key mechanisms that regulate cerebral blood flow at the local and systemic level (i.e., cerebral autoregulation and baroreflex sensitivity, respectively) may promote cerebral hypoperfusion in the course of normal activities of daily living, thereby setting the stage for repeated ischemic insults, progressive cognitive decline, and Alzheimer's disease and related dementias (ADRD). Thus, measuring cerebral autoregulation and baroreflex sensitivity may provide early biomarkers of neurodegeneration in ADRD studies, particularly those focused on prevention. The U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER) is an ongoing multi-center randomized clinical trial designed to investigate whether randomization to one of two lifestyle interventions that differ in format and intensity alters cognitive trajectory over 2 years in 2,000 older adults aged 60-79 years who are cognitively normal but at increased risk for dementia due to first degree family history of significant memory impairment, sedentary lifestyle, poor diet, and suboptimum cardiometabolic health. The proposed ancillary study POINTER-NV will comprehensively assess autonomic function, cerebral autoregulation, and vascular structure and function by evaluating aortic, carotid, and cerebral hemodynamics using complementary techniques (i.e., ultrasound, tonometry, and continuous blood pressure and heart rate monitoring) under a variety of conditions (i.e., at rest, during orthostatic stress, and during carbon dioxide inhalation). These neurovascular outcomes will be assessed at baseline, Year 1, and Year 2 in 500 POINTER participants across 5 clinical sites (~100 per site; 250 per intervention arm). The primary aim is to assess the effects of the POINTER lifestyle intervention on cerebral autoregulation and baroreflex sensitivity; we will also assess intervention effects on aortic stiffness, carotid stiffness, and cerebral vasomotor reactivity. In addition, POINTER-NV will examine whether these neurovascular outcomes are associated with cognition (assessed every 6 months as part of the parent trial) and brain structure and function (assessed every 1-2 years as part of a Brain Imaging ancillary study). By leveraging the rich resources and infrastructure of U.S. POINTER, this innovative and cost-effective ancillary study presents an unprecedented and time-limited opportunity to expand the scope and impact of the parent trial and address key research priorities in the field.